Pharmacokinetics and pharmacodynamics of high doses of inhaled dry powder drugs.

For many years, administration of drugs by inhalation has been the mainstay treatment for obstructive respiratory disorders such as asthma and chronic obstructive pulmonary disease. Antibiotics and other drugs have been administered for decades as aerosols to treat other pulmonary disease in a clinical setting, but it was until the early 1980's that colistin was formally marketed as a solution for nebulization in Europe (Colomycin, Pharmax, Bexley). The solubility of other drugs and the size of the dose required to achieve therapeutic concentrations at the site of action, made treatment times long and difficult to be performed at home. High dose dry powder delivery is a potentially effective way to deliver low potency drugs such as antibiotics. There are three major barriers to achieving the desired pharmacodynamic effect with these compounds: aerosol delivery, lung deposition and clearance. The powder formulation and device technology influence aerosol generation and may influence the size of the dose that can be achieved by inhalation in one puff. The site of deposition in the lungs is dictated by mechanisms of deposition which are influenced by the aerosol properties, particularly aerodynamic particle size distribution and the anatomy and physiology of the lungs. Finally, mechanisms of clearance dictate the local and systemic disposition of the drug, which in turn affects its pharmacokinetics and ultimately the pharmacodynamic effect and efficacy of treatment. Each of these factors will be considered and the implications for antimicrobial agent delivery as a high dose delivery example will be given.